Summary: Researchers have created the most broadly protective antivenom reported to date by using human antibodies taken from a donor who developed immunity through years of controlled exposure to deadly snake venoms. A three-part formulation—two human antibodies combined with a small-molecule toxin inhibitor—protected mice against lethal doses from a range of elapid snakes, including black mambas, king cobras, and tiger snakes.
This three-component cocktail fully neutralized toxins from 13 of the 19 venomous species tested and provided partial protection against the remaining species in the panel. The team plans to advance testing in larger animals and to continue development toward broad, possibly universal, antivenoms for both elapids and viperids to benefit vulnerable, underserved communities globally.
Key Facts:
- Unique donor source: The antivenom is based on broadly neutralizing human antibodies isolated from a hyper-immune donor with a rare history of repeated venom exposure.
- Broad-spectrum protection: A three-part combination achieved full protection against 13 dangerous elapid species and partial protection against the remainder of the test panel.
- Global health potential: The approach could lead to universal antivenoms that are less species-specific and better suited to regions that currently lack effective treatments.
Source: Cell Press
Using human antibodies recovered from a donor with long-term, self-administered exposure to snake neurotoxins, researchers have engineered a broadly effective antivenom that, in mouse trials, neutralized venoms from highly lethal elapid snakes such as the black mamba, king cobra, and tiger snakes.
Published May 2 in the journal Cell, the study demonstrates that combining targeted human antibodies with a small-molecule inhibitor can yield a compact, potent antivenom cocktail and lays the groundwork for developing broadly protective antiserums.
Traditional antivenom production has changed little in a century: animals such as horses or sheep are immunized with a particular snake’s venom and the resulting animal antibodies are harvested to treat human envenomation. Although this method can be effective, it often produces non-human antibodies that cause adverse reactions and usually yields treatments that are specific to certain species or regions.
In searching for alternatives, the research team identified a rare human donor with exceptionally broad immunity to snake neurotoxins. The donor, Tim Friede, had, over nearly 18 years, repeatedly exposed himself to escalating doses of venoms from 16 highly dangerous snake species—exposures that would normally be fatal to other animals such as horses, according to the study’s authors.
After the donor agreed to participate, researchers analyzed his immune memory and isolated antibodies that recognized and neutralized multiple classes of neurotoxins. Those broadly neutralizing antibodies became the basis for constructing a minimal yet effective antivenom cocktail.
To evaluate breadth of protection, the team assembled a test panel of 19 World Health Organization Category 1 and 2 elapid species. Elapids include many of the world’s most dangerous snakes—coral snakes, mambas, cobras, taipans, and kraits—and account for a large fraction of venomous species globally.
From the donor’s blood, scientists recovered antibodies that bound conserved neutralizing sites on long and short neurotoxins common across those species. Each antibody was tested sequentially in mice that had been injected with whole venom from each species in the panel, enabling the researchers to assemble a cocktail with the minimum number of components required for broad protection.
The final formulation contained two human antibodies—identified as LNX-D09 and SNX-B03—and the small-molecule phospholipase A2 inhibitor varespladib. LNX-D09 alone neutralized whole-venom lethality from six species. Adding varespladib extended protection to three more species, and the inclusion of SNX-B03 broadened protection across the full panel.
“With three components we achieved an unprecedented breadth of full protection for 13 of the 19 species and partial protection for the remainder,” said first author Jacob Glanville, CEO of Centivax, Inc. The team explored whether a fourth agent might further increase coverage, but even the compact three-part cocktail appears likely to protect against many additional elapid species beyond those tested.
Following these promising mouse trials, researchers aim to move into field-relevant testing. The next step will involve evaluating safety and efficacy in dogs treated at veterinary clinics after snakebites in Australia, followed by iterative development of similar broad-spectrum approaches for viperid venoms.
“We are now preparing reagents and carrying out iterative studies to determine the minimal, sufficient cocktail that provides broad protection against viperid venoms,” said lead author Peter Kwong, Richard J. Stock Professor of Medical Sciences at Columbia University Vagelos College of Physicians and Surgeons. The ultimate goal is either a single pan-antivenom or two complementary products—one targeting elapids and another for viperids—depending on regional needs.
Securing funding and manufacturing support will be critical to translate this research into widely available treatments. The authors emphasize that while millions of snake envenomations occur each year, most happen in low- and middle-income countries and disproportionately affect rural communities with limited access to effective antivenoms.
Funding:
This research received support from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, the NIH Small Business Innovation Research (SBIR) program, and the U.S. Department of Energy.
About this neuroscience and neurotoxin research news
Author: Jordan Greer
Source: Cell Press
Contact: Jordan Greer – Cell Press
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Snake-venom protection by a cocktail of varespladib and broadly neutralizing human antibodies” by Jacob Glanville et al. Cell
Abstract
Snake-venom protection by a cocktail of varespladib and broadly neutralizing human antibodies
Snakebite envenoming is a neglected tropical disease that affects millions worldwide. Over 600 venomous species contribute to more than 100,000 deaths and roughly 300,000 cases of permanent disability each year. Broadly neutralizing antibodies and chemical inhibitors have been proposed as scalable solutions, but the optimal composition and minimal number of components needed for an effective therapeutic cocktail have been unclear.
To address this, the authors recovered two broadly neutralizing human antibodies from the memory B cells of a hyper-immune donor with extensive exposure to snake venoms. Structural studies showed these antibodies recognize conserved neutralizing epitopes on both long and short neurotoxins, and crystal structures revealed that the antibodies mimic interfaces used by those neurotoxins to bind the host nicotinic acetylcholine receptor.
Combined with the phospholipase A2 inhibitor varespladib, the two antibodies formed a three-component cocktail that rescued animals from whole-venom challenge across a 19-member WHO Category 1 and 2 elapid diversity set, providing complete protection against most species in the panel.